Study for Asymmetric Syntheses of Alkaloids with Nurotransmission Inhibitory Effects

全氢组蛋白可可毒素1（perhydrohistrioniocotoxin 1）是一种具有神经传递抑制作用的生物碱，其合成是通过Pummerer加成反应[1，2]和羰基烯丙基化反应完成的，在烯丙基溴化镁作用下，乙烯基亚砜2选择性地生成乙烯基硫醚3（90% e.e.）Pummerer加成反应新形成的季碳的绝对构型通过将其转化为（+）-马炔内酯而确定为S。然后，乙烯基硫醚3转化为醛4。钯催化的分子内羰基酰基化4进行非对映选择性地提供5所需的立体化学，从而同时构建三个连续的不对称碳中心。最后，将螺环化合物5转化为已知的中间体6。由于6通过Takahashi和同事[3]的方法在6个步骤中导致（+）-1，因此完成了（+）-1的形式合成。该合成路线为组蛋白毒素及其同系物的合成和构效关系的研究提供了参考。[1]C.岩田等人，J.Chem.Soc.，化学通讯，1991,1408. [2]C.岩田等人，同上，1991,1049. [3]K.Takahashi等人，Helv.Chim.Acta，1982，65，252.

Formal synthesis of perhydrohistrioniocotoxin 1, an alkaloid with the inhibitory effect against neurotransmission, was accomplished using an additive Pummerer reaction [1,2] and a carbonyl allylation reaction as crucial steps.On treatment with allylmagnesium bromide, the vinylic sulfoxide 2 gave selectively the vinylic sulfide 3 (90% e.e.) by additive Pummerer reaction. The absolute configuration of the newly formed quaternary carbon was determined as S by converting it into (+) -malyngolide. Then, the vinylic sulfide 3 was converted into the aldehyde 4. Palladium-catalyzed intramolecular carbonyl aflylation of 4 proceeded diastereoselectively to afford 5 with the desired stereochemistry, thereby constructing the three contiguous asymmetric carbon centers simultaneously. Finally, the spiro compound 5 was converted into the known intermediate 6. Since 6 leads to (+) -1 in 6 steps by the method of Takahashi and coworkers [3], a formal synthesis of (+) -1 was accomplished. This synthetic route may be useful for the syntheses of histrionicotoxin and congeners and for the research on structure-activity relationship.[1] C.Iwata et al., J.Chem.Soc., Chem.Commun., 1991,1408.[2] C.Iwata et al., ibid., 1991,1049.[3] K.Takahashi et al., Helv.Chim.Acta, 1982,65,252.